The focus of this research is to define immunologic and other cofactors to explain why cervical HPV infection (a common sexually-transmitted diseases) progresses in rare instances to high-grade neoplasia. Accompanying prevention research on HPV diagnostics attempts to improve cervical cytologic ("Pap smear") screening, while projects on HPV immunology attempt to complement ongoing worldwide vaccine development efforts by suggesting biomarkers correlated with good clinical outcomes following infection (i.e., natural protection). Several projects were completed in FY 1997. A comparison of women with high-grade cervical neoplasia to those infected with HPV, but not progressed to high-grade neoplasia, revealed two distinct serologic patterns related to risk. One risk group was seropositive to virus-like particles of HPV 16 and a correlated cluster of other antigens, while another distinct group was seropositive to HPV 16 E610 and a second cluster of antigens. The importance of this surprising "clustering" of responses is not yet known. Another immunologic investigation demonstrated that IL-2 receptor levels are increased in women with high-grade but still intraepithelial cervical neoplasia. The evidence is now overwhelming that there is a systemic immune response to still pre-invasive cervical lesions, although it often is not adequate to eliminate the lesions. In a prevention project, it was demonstrated that highly-accurate cervical screening is feasible using a single clinical collection. Specifically, if the cervical sampler is rinsed in a buffer (rather than smeared on the slide), the buffer-based cytologic preparation can be used to make a thin-layer preparation for excellent cytologic screening. This buffer-based collection can be used for HPV DNA diagnostic testing of the residual cells from equivocal cytologic cases. This combined approach virtually eliminates the old "Class 2" or "atypical" cytologic category that caused much clinical confusion.